Magnetic particles are used for a variety of separation, purification, and isolation techniques in connection with chemical or biological molecules. In those techniques, a magnetic particle is coupled to a molecule capable of forming a specific binding (“affinity binding”) with a molecule in a biological sample, which is to be isolated, purified or separated. The biological sample is then brought into contact with the magnetic particle and those biological molecules which bind to the magnetic particles are then isolated by application of a magnetic field.
Magnetic microparticles or nanoparticles are used to bind DNA molecules, proteins, cells, and sometimes subcellular fragments. In recent years, magnetic microparticles have been used as solid phase for chemical synthesis. Microparticles are in the size of 0.5-10 micron while nanoparticles are 0.05-0.3 micron.
Various devices and methods have been developed in order to separate and transfer magnetic particles. Generally, the available methods fall under two categories. In the first method, a specialized magnetic suspension vessel is contacted with a magnet, and particles move towards the magnet, thus becoming attached to the side of the vessel. The remaining liquid is removed out of the vessel via decantation or aspiration.
In the second method, cylindrical magnetic rods covered with protective plastic sleeves or tips are brought into direct contact with a magnetic suspension. Particles are captured on the rod while the liquid remains in vessel. The rod with captured particles is moved into another vessel. When the magnet is withdrawn out of the protective sleeve, particles detach from the tip into the vessel.
The second method is advantageous with respect to the first, since a stronger magnetic field is applied directly on the particles, and therefore, nearly all of the particles are captured. Another advantage is that since the particles are readily transferred to a second vessel, removal of liquid in the source vessel is not needed, and one step has been saved.
Patent No. EP 0787296 to Tuunanen describes a magnetic rod device for the separation of microparticles. The tip of the device is shaped like a cone for transferring particles from large volumes into smaller volumes. The device, however, is only useful for separating one sample at a time.
U.S Pat. No. 6,409,925 to Gombinsky et al. describes a system of magnetic rod devices wherein each device in the system is independently controlled. Thus, any desired combination of magnetic rods can be operated. The magnets in this system are operated via pneumatic forces that are automatically controlled. The system permits transfer of specific combinations of magnetic particles and thus it can be used for combinatorial chemical synthesis. A magnetic plate is provided beneath the microtiter plates for facilitating separation of the magnetic particles from the tip into liquid in the well.
U.S. Pat. No. 6,468,810 to Korpela describes a similar rod device for capturing and releasing magnetic microparticles. The magnets in this device are operated via springs. An extendible membrane is provided as well as means for joining and separating the magnet with the first side of the membrane such that in operation the magnet is releasably pressed against the first side of the membrane, thereby stretching the membrane so that microparticles become fixed, by magnetic attraction, to the second side of the membrane. When the magnet is separated from the first side of the membrane, the particles become released from the second side.
In all of the aforementioned references, the magnetic rod moves inside of a static tube either electrically, pneumatically, or manually. The protective sleeve or tip covering the magnet is attached to the end of the static tube, and is detached or released from the tube by an outside mechanism, usually a manual arm attached to the outside surface of the tube.
U.S. Pat. No. 5,970,806 to Telimaa et al. relates to a multi-cylinder pipette comprising 16 4.5 mm spaced channels. The pipette is thus suitable only for use with a plate comprising 16×24, or 384 wells.
U.S. Pat. No. 6,235,244 to Allen et al. relates to a uniformly expandable multi-channel pipettor having a plurality of tip fittings whose spacing can be adjusted so that the spacing between each adjacent tip fitting is substantially identical. The device is known as the Equalizer 384 ™ by Matrix, and it allows the user to switch between microtiter plates of different sizes. The tip fittings are attached one to another by a linkage such as a pantographic linkage. The spacing is limited by an adjustable, slidable stop. Uniformly increasing and decreasing the spacing is accomplished by pulling and pushing a rod attached to one tip fitting. However, the Equalizer is a highly complicated device, and it is very expensive.
A disadvantage of prior art devices is that they cannot be used with microtiter plates of different sizes, only with one-size plates. Pipettor devices with eight connectors are for use with 96-well plates and pipettor devices with sixteen connectors are for use with 384-well plates. Patent EP 0787296 allows for the transfer of particles between microtiter plates having different sizes, but this is with the use of a single magnetic rod, and thus it cannot be used in combinatorial applications.
In light of the above, it would be desirable to provide a combinatorial device for the separation and transfer of magnetic particles or liquids that can be used with microtiter plates of different well sizes, and that would allow the user to determine the exact combination of samples that are to be separated and transferred.